DESCRIPTION(Applicant's abstract reproduced verbatim): The mammalian CNS contains many different types of neurons and glia, and each plays a specific role in regulating movement, perception, cognition, and overall behavior. It is clinically important to understand how different neural cell types are generated, because it may help us recognize the primary defect in neuro-degenerative diseases, cancers of the nervous system, or behavioral disorders. Defining the molecular/genetic basis of a neural disorder is vital for developing appropriate therapeutic interventions. We are using Drosophila as a model system for understanding how neural diversity is generated. Recent work has shown that Drosophila and mammals share a surprising degree of conservation in the mechanisms regulating neurogenesis. Thus, Drosophila research is an efficient means for uncovering clinically relevant genes. The three specific aims of the research proposed here are to: (1) Identify and characterize genes that establish different neural cell types along the dorsoventral axis of the CNS. Mammalian motoneurons, interneurons, and sensory neurons develop from distinct regions along the dorsoventral axis of the CNS. In Drosophila, there are also differences in the neural cell types along the dorsoventral axis, but very little is known about the mechanisms used to generate these distinct neural fates. (2) Identify and characterize genes that establish different neural cell types produced by individual stem cells. In mammals, a single cerebral cortical stem cell can generate neurons with distinct laminar fates; in Drosophila, a single neural stem cell (neuroblast) also generates a characteristic lineage of neurons and glia with diverse morphology and function within the CNS. We would like to understand how one stem cell can produce multiple, neuronal and glial cell types. (3) Characterize the newly discovered Sanpodo/Notch signaling pathway. The Notch signaling pathway is an evolutionarily conserved mechanism for modulating cell fate in Drosophila and mammals; in addition, Notch mutations can cause leukemia and other human diseases. Our data indicate that Sanpodo is an actin-binding protein necessary for many Notch-dependent signaling events within the Drosophila CNS. We plan to further characterize the molecular, genetic, and biochemical function of Drosophila and human Sanpodo genes in regulating Notch signaling.